The inflammatory bowel diseases, Crohn's disease and ulcerative colitis, are chronic frequently disabling inflammatory disorders of the small and large intestines. Despite extensive immunologic, pathologic and microbiologic reseerch, the etiology remains unknown, and the pathophysiology is poorly understood. Medical therapy is suboptimal and often associated with considerable morbidity. The risk of colorectal cancer is significantly increased for both disorders. There is strong evidence from twin studies, studies of familial aggregation and ethnic differences in disese prevalence that the inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC), are in large part genetic. The disorders are categorized as complex genetic disorders, since inheritance does not follow simple Mendelian patterns. In comparison with other complex genetic disorders the degree of genetic clustering in siblings, expressed as ns and defined as the increased risk over population prevalence for a sibling of a proband, is relatively large. ns for CD, UC and IBD have been estimated at 36.5, 16.6 and 24.7, respectively, comparatively greater than that for other disorders where susceptibility genes have been better established, such as IDDM and schizophrenia where ns is 15 and 8.6, respectively. CD and UC are genetically related as the cross disease relative risk is 3.85 with a CD proband and 1.72 with a UC proband. Our genetic studies on IBD are based on the hypothesis that there are specific susceptibility genes which are responsible for the familial clustering of these diseases. Susceptibility gene identification will allow an understanding of the initial pathophysiologic mechanisrns, and thus make it possible to design better medical therapy and better predict the disease course.